Dataset Information

Integrase inhibitor (INI) genotypic resistance in treatment-naive and raltegravir-experienced patients infected with diverse HIV-1 clades.

ABSTRACT:

Objectives

The aim of this study was to characterize the prevalence and patterns of genotypic integrase inhibitor (INI) resistance in relation to HIV-1 clade.

Methods

The cohort comprised 533 INI-naive subjects and 255 raltegravir recipients with viraemia who underwent integrase sequencing in routine care across Europe, including 134/533 (25.1%) and 46/255 (18.0%), respectively, with non-B clades (A, C, D, F, G, CRF01, CRF02, other CRFs, complex).

Results

No major INI resistance-associated mutations (RAMs) occurred in INI-naive subjects. Among raltegravir recipients with viraemia (median 3523 HIV-1 RNA copies/mL), 113/255 (44.3%) had one or more major INI RAMs, most commonly N155H (45/255, 17.6%), Q148H/R/K?+?G140S/A (35/255, 13.7%) and Y143R/C/H (12/255, 4.7%). In addition, four (1.6%) raltegravir recipients showed novel mutations at recognized resistance sites (E92A, S147I, N155D, N155Q) and novel mutations at other integrase positions that were statistically associated with raltegravir exposure (K159Q/R, I161L/M/T/V, E170A/G). Comparing subtype B with non-B clades, Q148H/R/K occurred in 42/209 (20.1%) versus 2/46 (4.3%) subjects (P?=?0.009) and G140S/A occurred in 36/209 (17.2%) versus 1/46 (2.2%) subjects (P?=?0.005). Intermediate- to high-level cross-resistance to twice-daily dolutegravir was predicted in 40/255 (15.7%) subjects, more commonly in subtype B versus non-B clades (39/209, 18.7% versus 1/46, 2.2%; P?=?0.003). A glycine (G) to serine (S) substitution at integrase position 140 required one nucleotide change in subtype B and two nucleotide changes in all non-B clades.

Conclusions

No major INI resistance mutations occurred in INI-naive subjects. Reduced occurrence of Q148H/R/K?+?G140S/A was seen in non-B clades versus subtype B, and was explained by the higher genetic barrier to the G140S mutation observed in all non-B clades analysed.

SUBMITTER: Doyle T

PROVIDER: S-EPMC4613743 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Publications

Integrase inhibitor (INI) genotypic resistance in treatment-naive and raltegravir-experienced patients infected with diverse HIV-1 clades.

Doyle Tomas T Dunn David T DT Ceccherini-Silberstein Francesca F De Mendoza Carmen C Garcia Frederico F Smit Erasmus E Fearnhill Esther E Marcelin Anne-Genevieve AG Martinez-Picado Javier J Kaiser Rolf R Geretti Anna Maria AM

The Journal of antimicrobial chemotherapy 20150826 11

<h4>Objectives</h4>The aim of this study was to characterize the prevalence and patterns of genotypic integrase inhibitor (INI) resistance in relation to HIV-1 clade.<h4>Methods</h4>The cohort comprised 533 INI-naive subjects and 255 raltegravir recipients with viraemia who underwent integrase sequencing in routine care across Europe, including 134/533 (25.1%) and 46/255 (18.0%), respectively, with non-B clades (A, C, D, F, G, CRF01, CRF02, other CRFs, complex).<h4>Results</h4>No major INI resis ...[more]

PMID: 26311843

Similar Datasets

Project description:There has been no systematic review of the prevalence of transmitted integrase strand transfer inhibitor (INSTI) resistance. We systematically searched the English-language PubMed database and GenBank to identify studies published since 2010 reporting 50 or more INSTI-naive HIV-1-infected adults undergoing integrase genotyping. We extracted data related to country, sample year, specimen type, sequencing method, and subtype. For studies with sequences in GenBank, we determined the prevalence of three categories of INSTI-associated resistance mutations: (1) nonpolymorphic INSTI-selected drug resistance mutations (DRMs) that we refer to as surveillance DRMs; (2) rarely selected nonpolymorphic INSTI-associated DRMs; and (3) common polymorphic accessory INSTI-selected DRMs. A total of 103 studies met inclusion criteria including 75 studies in GenBank containing integrase sequences from 16,481 INSTI-naive persons. The median sample year was 2013 (interquartile range: 2008-2014). The prevalence of INSTI surveillance DRMs, rarely selected DRMs, and common polymorphic accessory INSTI-selected DRMs were 0.5%, 0.8%, and 6.2%, respectively. There was no association between the presence of nonpolymorphic surveillance DRM and region, sample year, or subtype. Two surveillance DRMs, E138K and R263K occurred in 0.15% and 0.10% of naive sequences, respectively. Several lines of evidence suggested that the 0.5% prevalence of surveillance DRMs partly reflects the cumulative natural occurrence of these mutations in the absence of selective drug pressure. There was an unexplained temporal increase in the proportion of sequences with polymorphic accessory mutations. The prevalence of INSTI-associated surveillance DRMs is low even in regions where INSTIs have been a major component of antiretroviral therapy for several years. The presence of INSTI-associated surveillance DRMs in INSTI-naive persons likely results from actual cases of transmitted INSTI resistance and from a low background level reflecting the cumulative rare natural occurrence of several nonpolymorphic mutations.

Dataset Information

Integrase inhibitor (INI) genotypic resistance in treatment-naive and raltegravir-experienced patients infected with diverse HIV-1 clades.

Objectives

Methods

Results

Conclusions

Publications

Integrase inhibitor (INI) genotypic resistance in treatment-naive and raltegravir-experienced patients infected with diverse HIV-1 clades.

Similar Datasets

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